Proper formation of the cerebral cortex depends on an orderly production of a large number of neurons during embryonic development. Recent studies have convincingly shown that radial glial cells are a major population of neuronal progenitor cells in the developing cortex. In addition to their well-characterized role in guiding radial migration of newly born neurons, radial glial cells divide in the ventricular zone to generate neurons. Precise control of radial glial cell division in the developing cortex is likely a major factor in controlling the number of neurons in the mature cerebral cortex. Despite this fundamental role in cortical development, the mechanisms that regulate radial glial cell division are poorly understood. The long-term goal of this project is to elucidate the molecular and cellular processes underlying radial glial cell division and daughter cell fate specification. During peak neurogenesis, radial glial cells predominantly divide asymmetrically to self-renew and to generate neurons. Asymmetric cell division usually requires the dividing cells to be polarized so as to ensure differential inheritance of cell fate determinants by the two daughter cells. The objectives of this proposal are to uncover the molecular control of radial glial cell polarity and to define how the polarization of radial glial cells may regulate the mode of their division (i.e. being symmetric or asymmetric) in the developing cortex. Radial glial cells originate from epithelial cells that are highly polarized with distinct apical and basal subcellular compartments. This apical-basal polarity is controlled by a set of evolutionarily conserved protein complexes, among which the Par (partition defective) protein complex plays a central role. Moreover, the Par protein complex is essential for polarizing neural progenitor cells (i.e. neuroblasts and sensory organ precursors, SOPs) in the Drosophila nervous system and ensuring their asymmetric cell division. Based on these observations, the central hypothesis of this application is that the mammalian Par (mPar) protein complex controls the polarity and the division mode of radial glial cells in the developing cortex. Guided by strong preliminary data, this hypothesis will be tested by pursuing these three specific aims: 1) To determine the subcellular localization of the mPar protein complex in dividing radial glial cells; 2) To define the function of the mPar protein complex in regulating radial glial cell division and daughter cell fate specification; and 3) To delineate the molecular and cellular pathways of the mPar protein complex in the developing cortex. The approach is innovative, because it combines advanced laser scanning microscopy with molecular genetics techniques. The proposed research will provide new insights concerning how neuronal progenitor cells in the developing cortex divide to give rise to neurons. Many human neurological and psychiatric disorders are associated with defects in cortical neurogenesis, ranging from severe malformations with mental retardation and epilepsy, to more subtle ones such as autism and maladaptive behavior associated with drug abuse. The results of this study may shed light on mechanisms relevant to the etiology of many of these disorders. PUBLIC HEALTH RELEVANCE: This study investigates the processes underlying how neuronal progenitor cells divide to give rise to neurons in the developing brain, an important and under-investigated area in neuroscience. It will advance and expand the understanding and treatment of a variety of neurological and psychiatric disorders caused through defects in cerebral cortex development, such as mental retardation, epilepsy, autism, and maladaptive decision- making behavior associated with drug abuse.